1、Non-ST Elevation Acute Coronary Syndromes,Peter Berger, MD Professor of Medicine Dir. Of Interventional CardiologyDuke University Medical Center and Duke Clinical Research Institute Durham, NC China October, 2005,1.7 Million Hospital Discharges,AHA. Heart Disease and Stroke Statistics2005 Update,ACS

2、,STEMI,Hospital Discharges for ACS Non-STE ACS vs STEMI,NSTE ACS,1.4 Million Discharges/Yr,321,000 Discharge/Yr,NSTE ACS : Key Themes,NSTE ACS: a high risk population patient risk benefit from treatment with medications, an invasive strategy Interaction between invasive strategy and pharmacologic tx

3、 Antithrombotics cornerstone of treatment Anticoagulants: heparin, LMWH, direct thrombin inhibitors Antiplatelet agents: aspirin, IIb/IIIa, ADP inhibitors,Baseline Characteristics NSTE ACS Patients:Recent RCTs and Large Registry,Q2 2003 PURSUITCUREGUSTO-IV ACSCRUSADE Characteristic (n = 9,461)(n = 1

4、2,562) (n = 7,800) (n = 5,426) Mean age SD (yrs)63 1163 1265 1167 14 Diabetes mellitus (%)23232233 Prior CHF (%)11 8819 Prior PCI (%)13-1022 Prior CABG (%)1218*820,NEJM 1998;339:436; NEJM 2001;345:494 ; Lancet 2001;357:1915-24,* CABG or PTCA,Antman EM et al N Engl J Med 1996;335:1342-9,360,240,120,0

5、,20,18,16,14,12,10,8,6,4,2,0,Cumulative probability of death,84 ml/min,51-66 ml/min,51 ml/min,P0.001, log rank,%,66-84 ml/min,Aviles RJ et al NEJM 2003,Creatinine Clearance and Mortality GUSTO 4,Days,360,240,120,0,20,18,16,14,12,10,8,6,4,2,0,Probability of death, %,1869 ng/L,237-669 ng/L, 237 ng/L,P

6、0.001, log rank,669-1869 ng/L,James S et al Circulation 2003,NT-pro BNP GUSTO 4,Days,Invasive vs. Conservative Strategy for ACSDeath or (re)-MI,Trial N PCI Cons RITA 3 1810 7.6 8.3 VINO 131 6.3 22.4 TACTICS 2220 7.3 9.5 TRUCS 148 7.6 16.7 FRISC II 2451 10.4 14.1 MATE 201 9.9 6.7 VANQUISH 920 24.0 12

7、.2 Overall 7876,Fox, Lancet 360:743 03,Death/(re)-MI,CP971744-45,%,TACTICSTIMI 18,TnT cut point = 0.01 ng/mL (54% of pt TnT +),Troponin T: Death, MI, Rehosp ACS, 6 Months,OR=0.52 *P0.001 Interaction P0.001,P=NS,*,n=414,n=396,n=463,n=495,FRISC Score and an Invasive Strategy,Score 0-2 3-4 5-7 n 972 10

8、51 264 p 0.56 0.018 0.001 RR 1.14 (0.73-1.77) 0.69 (0.50-0.94) 0.44 (0.28-0.69),0,5,10,15,20,25,30,35,40,Death or MI at 12 mos, % Strategy:,Non-invasive,Invasive,FRISC score Age 65 years Male gender Diabetes mellitus Previous MI ST-depression Elevated troponin Elevated Il-6 / CRP,Lagerqvist B et al

9、Heart 2004,Benefits of an Invasive Strategy in Non-ST Elevation ACS,Only shown to reduce death and MI in high risk pts Reduces re-hospitalization, angina in many others Shortens hospitalization, may be cost effective What about the optimal timing of an invasive strategy?,Medical Tx for 72-170 hr The

10、n, cath lab n=207,Cath lab 6 hr n=203,ISAR-COOL,CP1107655-4,Neumann FJ et al JAMA 2004,67% had troponin, 65% had ST depression,Aspirin500 mg, 100 mg bid Clopidogrel600 mg, 75 mg bid Tirofiban10 mg/kg bolus, 0.10 mg/kg/min infusion Heparin(PTT 60-85 seconds),Non-ST Acute Coronary Syndrome troponin or

11、 ST depression n=410,ISAR-COOLPrimary Endpoint,CP1107655-2,30-day event rate (%),Death 324:7186.,OR*,0.5,1.0,1.5,2.0,5001500 mg34 19 160325 mg19 26 75150 mg12 32 75 mg3 13 Any aspirin65 23,Antiplatelet Better,Antiplatelet Worse,Aspirin DoseNo. of Trials(%),Odds Ratio,0,Aspirin Dose and Events in Hig

12、h-Risk PtsFrequency of CV Death, MI, Stroke,P=0.0001,CURE,CP999547-2,Yusuf S et al NEJM 2001;16:494-502,Non-ST elevation ACS 12,562 patients,ASA 75 to 325 mg po qd placebo n=6,303,3-12 month follow-up (average 9 mo),ASA + clopidogrel (300 mg load, 75 mg qd) n=6,259,CURE: Aspirin Dose and Outcome,%,(

13、N = 1,927),(N = 7,428),(N = 3,201),ASA/Clopidogrel ASA/Placebo,CV Death, MI, Stroke,Major Bleeding,Aspirin in ACS,More bleeding with higher doses, especially when combined with clopidogrel, coumadin Possibly greater efficacy with lower doses (not sure) I recommend: 165 mg once daily Guidelines: stil

14、l recommend 81-365 mg aspirin,CURECV Death/MI/Stroke, 1 Year,CP999731-3,CV death, MI, stroke (%),Clopidogrel (n=6,303),Placebo (n=6,259),P=0.00003,Days after enrollment,CURE,Eventrate(%),RR 0.80 P=0.00005,CP995058-6,CV death,MI, stroke,CVdeath,MI,Stroke,Non-CVdeath,RR 0.92 P=NS,RR 0.77 P0.001,RR 0.8

15、5 P=NS,RR 0.96 P=NS,Restricted the participation of hospitals that pursue an invasive strategy in the majority of ACS pts The results ought to be applied to pts that resemble those enrolled in the trial There is reason to believe that early dual antiplatelet therapy might have different safety, effi

16、cacy in invasive vs. non-invasively managed pts,CURE,CUREMajor/Life-Threatening Bleeds in the 7 Days After CABG,Major Bleeds: Significantly disabling, intraocular, or transfusion 2 units Life Threatening: Hgb 5g/dl, hypotension (inotropes), surgery to stop bleeding, symptomatic ICH or transfusion 4

17、units,ACC/AHA ACS Guideline Update,Class I ASA and clopidogrel for 9 months after NSTE ACS (level of evidence: B) Class 3 Do not administer clopidogrel in the 5 days before CABG,Braunwald E, et al. ,Heparin (UF or LMW) in ACS Without ST Death or MI,UFH or LMWH ControlOR95% CI Theroux2/122

18、 (1.6%)4/121 (3.3%)0.500.10-2.53 Cohen0/371/32 (3.1%)0.120.01-5.89 RISC3/210 (1.4%)7/189 (3.7%)0.400.11-1.39 Cohen4/105 (3.8%)9/109 (8.2%)0.460.15-1.41 Holdright*42/154 (27.3%)40/131 (30.5%)0.850.51-1.43 Gurfinkel4/70 (5.7%)7/73 (9.6%)0.580.17-1.98(UFH) Gurfinkel0/687/73 (9.6%)0.130.03-0.60(LMWH) FR

19、ISC4/70 (5.7%)36/757 (4.8%)0.390.22-0.68 UFH vs55/698 (7.9%)68/655 (10.4%)0.670.45-0.99placebo/control LMWH vs13/809 (1.6%)43/830 (5.2%)0.340.20-0.58placebo Total68/1507 (4.5%)104/1412 (7.4%)0.530.38-0.73,Only RCTs, placebo or untreated controlsEikelboom JW et al: Lancet 55:1936-42, 2000,CP951342-1,

20、0.1 Heparin better,1.0,10.0 Control better,EnoxaparinUFH(n = 4993)(n = 4985) Cath during hosp (%)9292 Time to cath*2221 (hours) (6, 44)(6, 43) PCI4747 Time to PCI*2322 (hours) (6, 49)(6, 48) CABG (%)1918 Time to CABG* 9189 (hours)(44, 167)(45, 166) Days hospitalized*54 (3, 8)(3, 8),In-hospital Proce

21、dures,*Median (25th ,75th),SYNERGY Death or MI at 30 Days,HR 0.96 (0.86-1.06),1.1,SYNERGYBleeding Events,EnoxaparinUFH(n = 4993)(n = 4985)P-value GUSTO severe07 TIMI major - clinical: 08 CABG-related81 Non-CABG-related25 Any RBC transfusion17.016.00.155 ICH 0.1 0.

22、1NS,PCI Patients: Thrombotic Complications,EnoxaparinUFH(n = 2321)(n = 2364) Unsuccessful PCI (%)3.63.4 Threatened abrupt closure (%)1.11.0 Abrupt closure (%)1.31.7 Emergency CABG (%)0.30.3,Elective PCI via Femoral Route N=3528,IV Enoxaparin 0.5 mg/kg bolus,IV Heparin 70-100 U/kg w/o IIb/IIIA (ACT 3

23、00-350) 50-70 U/kg with IIb/IIIa (ACT 200-300),STEEPLE,IV Enoxaparin 0.75 mg/kg bolus,Stratified by IIb/IIIa use,Montalescot G ESC 2005,STEEPLEBleeding at 48 Hrs (Primary End Point),Montalescot G ESC 2005,STEEPLEIschemic End Points at 30 Days,Montalescot G ESC 2005,Trial: FRIC (dalteparin; n=1482) F

24、RAXIS (nadroparin; n=2357) ESSENCE (enoxaparin; n=3171) TIMI IIB (enoxaparin; n=3910),.751.01.5,(P=0.032),(P=0.029),Braunwald E et al.Circulation 2000;102:1193-1209,LMWH Better,UFH Better,LMWH versus UFH in UA/NSTEMI Managed Non-invasively:Effect on Death, MI, Recurrent Ischemia,Rest pain 5 min and

25、ST 0.1 mV or Documented CAD or CK-MB N=132,Heparin 70 U/kg bolus + 15 U/kg/hr infusion,Bivalirudin 0.1 mg/kg bolus + 0.25 mg/kg infusion,TIMI - 8: Bivalirudin vs. Placebo in ACS,TIMI - 8: Bivalirudin vs. Placebo in ACS,4-6 wks,7 days,4-6 wks,7 days,p=0.008,p=0.024,p=NS,p=NS,Direct Thrombin Inhibitor

26、s in ACS,CP999731-7,Being studied; currently little data Do use a DTI in ACS pts with heparin induced thrombocytopenia Bivalirudin if an invasive strategy is planned (safe but not approved for HIT) Lepirudin if a non-invasive strategy is planned (approved for HIT, not approved for PCI),Beta Blockers

27、,Reduce CV death, MI, stroke by 25-30% in high risk pts Not well studied in non-STE ACS Reduce heart rate, blood pressure, ischemia, chest discomfort Class 1 indication; quality indicator Use in everyone without contraindications,Platelet GP IIb/IIIa Inhibition for Non-ST ACSPrimary Endpoint Results

28、 from the 5 Major RCTs,All PCI trials17,3930.668.55.6 All ACS trials24,3110.8912.811.4 ACS troponin (+)1,3680.4216.36.9 ACS PCI2,3110.6614.49.6 ACS no PCI12,6850.9314.313.3 ACS troponin ()2,9011.056.26.5,IIb/IIIa Meta-Analysis30-Day Death, MI at 30 Days,CP944328- 1,RelativeriskPlaceboIIb/IIIaNo.rati

29、o(%)(%),Chew DP et al: JACC 2000;36:2028 35,IIb/IIIa better,Placebo better,IIb/IIIa Inhibitors in ACS Patients,Greatest benefit is during PCI If pursuing a non-invasive strategy, recommend treating pts with elevated troponins, high TIMI, FRISC scores, etc; probably those with diabetes, marked ST segment shifts Do n